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Publication numberUS4874500 A
Publication typeGrant
Application numberUS 07/073,805
Publication dateOct 17, 1989
Filing dateJul 15, 1987
Priority dateJul 15, 1987
Fee statusPaid
Also published asCA1298873C, EP0299778A2, EP0299778A3
Publication number07073805, 073805, US 4874500 A, US 4874500A, US-A-4874500, US4874500 A, US4874500A
InventorsMarc J. Madou, Takaaki Otagawa
Original AssigneeSri International
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Monolithic substrate, conductor and electrodes
US 4874500 A
Abstract
The invention relates to a microelectrochemical electrode structure comprising a monolithic substrate having a front surface and a back surface facing generally away from one another, a first well extending into the substrate from the surface towards the back surface and ending in a first well bottom, and a first passage extending into the substrate from the back surface to the first well bottom. A first electrode is located wholly within the first well. A first conductor in the first passage serves for electrically communicating the first electrode to adjacent the back surface. A plurality of such electrode structures can be provided on a single substrate. The use of semiconductor processing technology allows the entire sensor to be extremely small. If desired, an integrated circuit can be provided on the back surface of the substrate for amplifying or otherwise processing signals from the first electrode. Analysis can be carried out for vapors or dissolved species (ionic or non-ionic).
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Claims(54)
We claim:
1. A microelectrochemical electrode structure, comprising:
a monolithic substrate having a front surface and a back surface facing generally away from one another, a first well extending into said substrate from said front surface towards said back surface and ending in a first well bottom, and a first passage extending into said substrate from said back surface to said first well bottom;
a first electrode wholly between said front and back surfaces of said substrate; and
a first conductor in said first passage electrically communicating said first electrode to adjacent said back surface.
2. An electrode structure as set forth in claim 1, further including:
an electrolytic medium in said first well;
a barrier having an outfacing surface and an infacing surface covering said first well with said infacing surface in flow contact with said electrolytic medium, said barrier providing entry into said electrolytic medium of a selected moiety in response to contact of a selected species with said outfacing surface and being at least substantially impermeable to said electrolytic medium.
3. An electrode structure as set forth in claim 2, wherein said first well extends sufficiently towards said back surface and said first electrode is sufficiently deeply positioned in said first well whereby electrochemical reaction of said moiety at said first electrode provides a substantially Nernstian slope.
4. An electrode structure as set forth in claim 3, wherein:
said substrate has a reference well extending into said substrate from said first surface towards said back surface and ending in a reference well bottom and a reference passage extending from said back surface to said reference well bottom; and
a reference electrode in said reference well;
and further including:
a reference conductor in said reference passage electrically communicating said reference electrode to adjacent said back surface.
5. An electrode structure as set forth in claim 4, wherein:
said substrate has a counter well extending into said substrate from said surface towards said back surface and ending in a counter well bottom and a counter passage extending from said back surface to said counter well bottom; and
said counter electrode is in said counter well;
and further including:
a counter conductor in said counter passage electrically communicating said counter electrode to adjacent said back surface.
6. An electrode structure as set forth in claim 9, wherein said barrier further covers said reference well and said counter well.
7. An electrode structure as set forth in claim 2, wherein said electrolytic medium comprises a solid conductive polymer.
8. An electrode structure as set forth in claim 2, where said barrier comprises a gas pervious liquid impervious membrane.
9. A plurality of electrode structures as set forth in claim 5, wherein a sub-plurality of said plurality of electrode structures is sensitive to a single one of said selected species.
10. An electrode structure as set forth in claim 2, wherein said first well is a sensor well, said first well bottom is a sensor well bottom, said first passage is a sensor passage and said first electrode is a sensing electrode.
11. An electrode structure as set forth in claim 10, further including:
a reference electrode in electrical communication with said electrolytic medium and electrically isolated from said sensing electrode other than via said electrolytic medium.
12. An electrode structure as set forth in claim 11, further including:
electronic circuitry in said substrate adjacent said back surface adapted for processing signals from said sensing electrode and said reference electrode.
13. An electrode structure as set forth in claim 11, wherein:
said substrate has a reference passage extending from said back surface to said sensor well bottom; and
said reference electrode is wholly between said front and back surfaces of said substrate;
and further including:
a second conductor in said reference passage electrically communicating said reference electrode to adjacent said back surface.
14. A plurality of said electrode structures on said substrate, said plurality including a plurality of sensing electrodes and a plurality of reference electrodes as set forth in claim 13.
15. An electrode structure as set forth in claim 13, in combination with:
a separate member having electronic circuitry adapted for processing signals from said sensing electrode and said reference electrode and means for connecting said first and second conductors to said electronic circuitry,
16. An electrode structure as set forth in claim 11, further including:
a counter electrode in electrical communication with said electrolytic medium and electrically isolated from said sensing electrode and said reference electrode other than via said electrolytic medium.
17. An electrode structure as set forth in claim 16 wherein:
said substrate has a reference passage extending from said back surface to said sensor well bottom; and
said reference electrode is wholly between said front and back surfaces of said substrate;
and further including:
a second conductor in said reference passage electrically communicating said reference electrode to adjacent said back surface.
18. An electrode structure as set forth in claim 17, wherein:
said substrate has a counter passage extending from said back surface to said sensor well bottom; and
said counter electrode is wholly between said front and back surfaces of said substrate;
and further including:
a third conductor in said counter passage electrically communicating said counter electrode to adjacent said back surface.
19. A plurality of said electrode structures on said substrate, said plurality including a plurality of sensing electrodes and a plurality of counter electrodes as set forth in claim 18.
20. An electrode structure as set forth in claim 18, further including:
electronic circuitry in said substrate adjacent said back surface adapted for processing signals from said sensing electrode, said reference electrode and said counter electrode.
21. An electrode structure as set forth in claim 1, further including:
electronic circuitry in said substrate adjacent said back surface adapted for processing signals from said first electrode.
22. A plurality of electrode structures on said substrate, each of said electrode structures being as set forth in claim 1.
23. A plurality of electrode structures as set forth in claim 22, wherein a sub-plurality of said plurality of electrode structures is sensitive to a single one of said selected species.
24. A plurality of electrode structures as set forth in claim 22, said structures being arranged in adjacent relation and located along a straight line.
25. A plurality of electrode structures as set forth in claim 24, wherein said structures each have a width of no more than about 300 microns and said plurality has a length of no more than about 150 microns multiplied by the number of said structures.
26. A plurality of electrode structures as set forth in claim 24, further including:
one or more pressure sensors arranged in said straight line with said structures,
27. A plurality of electrode structures as set forth in claim 26, wherein said structures and said one or more pressure sensors each have a width of no more than about 300 microns and said plurality plus said one or more pressure sensor has a length of no more than about 150 microns multiplied by the number of said structures plus the number of said pressure sensors.
28. An electrode structure as set forth in claim 1, wherein said first well extends from about 40 to about 200 microns towards said back surface and wherein said back surface is from about 10 to about 100 microns from said first well bottom.
29. An electrode structure as set forth in claim 28 wherein said first well extends from about 60 to about 125 microns towards said back surface and wherein said back surface is from about 10 to about 40 microns from said first well bottom.
30. An electrode structure as set forth in claim 1, wherein said substrate is a semiconductor.
31. An electrode structure as set forth in claim 30, wherein said substrate is silicon, silicon carbide or gallium arsenide.
32. An electrode structure as set forth in claim 30, wherein said sensor well is formed by anisotropic etching and has sidewalls which form an obtuse angle with said front surface.
33. An electrode structure as set forth in claim 30, wherein said sensor well is formed by anisotropic etching and has sidewalls which form an obtuse angle with said front surface.
34. An electrode structure as set forth in claim 1, wherein said first electrode includes an electrode base and a conductive ion-selective member attached thereto and having an electroactive species incorporated therein.
35. An electrode structure as set forth in claim 34, wherein said first well extends sufficiently towards said back surface and said first electrode is sufficiently deeply positioned in said first well whereby electrochemical reaction of said moiety at said first electrode provides a substantially Nernstian slope.
36. An electrode structure as set forth in claim 34, further including:
electronic circuitry in said substrate adjacent said back surface adapted for processing signals from said first electrode.
37. An electrode structure as set forth in claim 34, wherein said substrate is silicon, silicon carbide or gallium arsenide.
38. A plurality of electrode structures on said substrate, said electrode structures being as set forth in claim 34.
39. An electrode structure as set forth in claim 34, wherein said substrate is a semiconductor.
40. An electrode structure as set forth in claim 34, wherein said first well extends from about 40 to about 200 microns towards said back surface and wherein said back surface is from about 10 to about 100 microns from said first well bottom.
41. An electrode structure as set forth in claim 34 wherein said first well extends from about 60 to about 125 microns towards said back surface and wherein said back surface is from about 10 to about 40 microns from said first well bottom.
42. An electrode structure as set forth in claim 34, wherein said first well is a sensor well, said first well bottom is a sensor well bottom, said first passage is a sensor passage, said first electrode is a sensing electrode and said first conductor is a sensor conductor.
43. An electrode structure as set forth in claim 42, wherein:
said substrate has a reference well extending into said substrate from said first surface towards said back surface and ending in a reference well bottom and a second passage extending from said back surface to said reference well bottom; and
a reference electrode in said reference well;
and further including:
a reference conductor in said second passage electrically communicating said reference electrode to adjacent said back surface.
44. An electrode structure as set forth in claim 43, wherein:
said substrate has a counter well extending into said substrate from said surface towards said back surface and ending in a counter well bottom and a third passage extending from said back surface to said counter well bottom; and
said counter electrode is in said counter and further including:
a counter conductor in said third passage electrically communicating said counter electrode to adjacent said back surface.
45. A plurality of said electrode structures on said substrate, said plurality including a plurality of sensing electrodes and a plurality of counter electrodes as set forth in claim 43.
46. An electrode structure as set forth in claim 42, further including:
an electrolytic medium in contact with said sensing electrode; and
a reference electrode in electrical communication with said electrolytic medium and electrically isolated from said sensing electrode other than via said electrolytic medium.
47. An electrode structure as set forth in claim 46, wherein said electrolytic medium comprises a solid conductor polymer.
48. An electrode structure as set forth in claim 46, further including:
electronic circuitry in said substrate adjacent said back surface adapted for processing signals from said sensing electrode and said reference electrode.
49. An electrode structure as set forth in claim 46, wherein:
said substrate has a second passage extending from said back surface to said sensor well bottom; and
said reference electrode is in said sensor well;
and further including:
a reference conductor in said second passage electrically communicating said reference electrode to adjacent said back surface.
50. A plurality of said electrode structures on said substrate, said plurality including a plurality of sensing electrodes and a plurality of reference electrodes as set forth in claim 49.
51. An electrode structure as set forth in claim 46, further including:
an electrolytic medium in contact with said sensing electrode; and
a counter electrode in electrical communication with said electrolytic medium and electrically isolated from said sensing electrode and said reference electrode other than via said electrolytic medium.
52. An electrode structure as set forth in claim 51 wherein:
said substrate has a second passage extending from said back surface to said sensor well bottom; and
said reference electrode is in said sensor well;
and further including:
a reference conductor in said second passage electrically communicating said reference electrode to adjacent said back surface.
53. An electrode structure as set forth in claim 52, wherein:
said substrate has a third passage extending from said back surface to said sensor well bottom; and
said counter electrode is in said sensor well;
and further including:
a counter conductor in said third passage electrically communicating said counter electrode to adjacent said back surface.
54. An electrode structure as set forth in claim 53, further including:
electronic circuitry in said substrate adjacent said back surface adapted for processing signals from said sensing electrode, said reference electrode and said counter electrode.
Description
TECHNICAL FIELD

The present invention relates to micro-electrochemical sensors useful for detecting various chemicals, including vaporous and gaseous species and dissolved species, in very low concentrations. The micro-electrochemical sensors themselves are formulated by integrated circuit (IC) engineering techniques and can be extremely small in size, namely, as small as one-fifth to one-sixth the size of the smallest previously known sensors. Among numerous other uses, they may be utilized to analyze blood chemistry, in vivo.

BACKGROUND ART

In a large number of situations it is desirable to be able to analyze a sample, be it a liquid sample or a gaseous sample, for one or more constituents. Often, it is desirable to analyze for several constituents at once. For example, it is desirable to be able to analyze blood for such diverse components as H+, K+, CO2 and O2, etc. It is also often desirable to be able to analyze air samples for air borne contaminants such as CO, NO, NO2, N2 O, SO2, H2 S and O2 and other gases as well.

Within the last several years a number of sensors have been developed based upon one or more of the techniques developed by integrated circuit engineering technology. For example, U.S. Pat. No. 4,020,830, issued May 3, 1977 to C. C. Johnson, et al, utilizes a chemical sensitive field-effect transistor (FET) transducer for selectively detecting and measuring chemical properties of substances to which the transducer is exposed. Basically, the chemical being detected interacts with certain substances to modulate the electric field produced in the substrate semiconductor material between diffusion regions thereof. Such FET devices have been demonstrated to be useable for detecting ions as well as gases, and indirectly certain dissolved molecules. However, fluctuations in drain current leading to errors are still a significant problem. These fluctuations can be associated with thermal noise or they can be light induced. Layers that make the FET chemically sensitive and selective are very difficult to deposit on the gates of such devices, especially since often several layers of different composition are needed. All of this leads to errors or makes fabrication difficult. Still further, reference electrodes are very difficult to implement in FET structures.

S. J. Pace, as set forth in U.S. Pat. No. 4,225,410, discloses a disposable integrated miniaturized array of chemical sensors for analyzing concurrently a number of analytes in a fluid sample. Each sensor of the array is a complete electrochemical cell having its own reference and indicator electrodes and is selective with respect to a particular analyte. The sensors are all formed on top of the surface of a substrate which is prepared by press forming powdered alumina with appropriate through holes and imprints for the electrochemical circuit. Because of the manufacturing techniques such sensors and sensor arrays must be relatively large and are more properly describable as minisensors rather than microsensors.

In U.S. Pat. No. 4,549,951, issued Oct. 29, 1985 to M. B. Knudson, et al, a relatively large, compared to both of the devices discussed above, ion selective electrode is set forth which is used along with a separate reference electrode. The ion-selective membrane of the electrode sits on a conductor embedded in a plastic substrate, This is basically a small ion-selective electrode with the membrane sitting on top of a conductor and without an internal reference electrolyte or true reference electrode. Further, construction of such an electrode design in micro sizes appears to be beyond the current state of the art.

In the devices of U.S. Pat. Nos. 4,020,830, 4,225,410, and 4,549,951 the entire electrochemical cell sits upon the surface of a substrate. This leads to a significant problem in providing proper encapsulation. In the case of U.S. Pat. No. 4,020,830, all of the electronic circuitry is included on the analyte detecting side of the FET. This leads to problems between the chemicals and the electronic circuitry which are either in contact with one another or closely adjacent to one another.

The prior art, including the above discussed patents, does not yet provide microelectrochemical sensors and sensor arrays incorporating both amperometric and potentiometric elements, which operate at room temperature and consume little power, which provide versatile, multi-purpose-multi-channel, real time monitoring of vapors, gases, molecules and ions, which are micro-portable and field rugged, which have fast response times at ambient temperature, which are free of interferences from such parameters as oxygen deficiency and humidity, which can be produced inexpensively using sophisticated modern micro-fabrication technologies, which have high specificity and high selectivity, for example, parts-per-billion level detection of such gases CO, NO, NO2, H2 S, SO2, and N2 H4 and parts-per-million detection of such gases as HCN, Cl2, H2, O2, C2 H5 OH, HCHO, C3 H3 N, O3, C2 H2, C2 H4, CH4, C2 H6, C3 H8, and organophosphate vapors, and which are adaptable for detecting ionic electroactive species in parts-per-billion in solutions, including, for example, Cl-, Br-, I-, SCN-, CN-, S2 O3 2-, OCl-, SO3 2-, phenols, aromatic amines, nitro compounds, organoarsines, and metal ions, e.g., Cu2+, Fe3+.

The present invention is directed to solving one or more of the problems as set forth above.

DISCLOSURE OF INVENTION

In one embodiment of the present invention a microelectrochemical electrode structure is set forth. The aforementioned electrode structure comprises a monolithic substrate having a front surface and a back surface facing generally away from one another. A first well extends into the substrate from the front surface towards the back surface and ends in a first well bottom. A first passage extends into the substrate from the back surface to the first well bottom. A first electrolytic cell including a first electrode is located wholly between the front and back surfaces of the substrate. A first conductor is located in the first passage and electrically communicates the first electrode to adjacent the back surface.

In accordance with one embodiment of the invention an electrolytic medium is in the first well. A barrier covers the first well, the barrier having an outfacing surface and an infacing surface. The infacing surface is in flow contact with the electrolytic medium. The barrier provides entry into the electrolytic medium of a selected moiety in response to contact of a selected species with the outfacing surface. The barrier is at least substantially impermeable to the electrolytic medium.

Another embodiment of the present invention is a sensor array including a plurality of such first electrode structures in the substrate.

Optionally, each electrode structure can have more than one electrode in the first well.

An electrode structure in accordance with the present invention is characterized by extremely small size, is operable at room temperature, utilizes low power, is field rugged, has a fast response time, is not sensitive to interferences due to oxygen deficiency or differences in humidity, can be readily mass produced using sophisticated microfabrication technologies, has high specificity and high selectivity, can have very short signal lines to signal amplification circuitry integrated and embedded in the back side of the substrate thereby providing a high signal-to-noise ratio, and is useful in accordance with specific embodiments to detect vapors, dissolved ions and dissolved nonionic species (including dissolved gases). The structure is also very well suited to having a pressure element incorporated in an array therewith. Because the geometric configuration of a resistive or capacitive sensor is so similar to the structure created for the chemical sensitive elements it only requires a few more processing steps to also include a pressure element on the same substrate. In some applications (e.g., biomedical) such added features are very beneficial.

In accordance with embodiments of the present invention a single substrate can have an array of one or more electrode structures, each sensitive for one or several of a number of different chemical species. And, the entire sensor array can be so small that it can be readily positioned in, for example, a catheter in the blood stream and can be used to give a constant readout of such chemicals as CO2, O2, K+, H+, and the like. In accordance with certain embodiments of the present invention it is possible to include integrated circuitry electronics on the back surface of the substrate removed from the electrochemistry whereby one can amplify the signals and/or obtain electrical output signals which are specifically indictive of the concentration of one or of a number of species. The electrode structure of the present invention can be designed to exhibit substantially Nernstian slopes for ionic species. The amperometric electrode structures of the present invention can be designed to exhibit substantially linear dependency on concentration. The bottom of the first well can be chosen to be at different distances from the front and back surfaces of the substrate for different intended applications.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood by reference to the figures of the drawings wherein like numbers denote like parts throughout and wherein:

FIG. 1 illustrates, in a side sectional view, an embodiment of a microelectrochemical sensor in accordance with an embodiment of the present invention;

FIG. 2 illustrates, in similar view, an alternate embodiment of the present invention;

FIG. 3 illustrates, in similar view, an alternate embodiment of the present invention;

FIG. 4 illustrates, in similar view, an alternate embodiment of the present invention;

FIG. 5 illustrates, in similar view; an alternate embodiment of the present invention;

FIG. 6 illustrates, in similar view, an alternate embodiment of the present invention;

FIG. 7 illustrates a detail in the embodiment of FIG. 6;

FIG. 8 illustrates, in similar view, an alternate embodiment of the present invention;

FIG. 9 illustrates, in plan view, an array of microelectrochemical sensors in accordance with an embodiment of the present invention;

FIG. 10 illustrates, in plan view, an alternate array of microelectrochemical sensors in accordance with an embodiment of the present invention;

FIG. 11 illustrates a side sectional view of a portion of FIG. 10 and shows the combination of an array of sensor elements with a pressure sensor;

FIG. 12 illustrates, in similar view to FIG. 1, an alternate embodiment of the present invention;

FIG. 13 illustrates, in similar view to FIG. 1, an alternate embodiment of the present invention; and

FIG. 14 illustrates, in a side sectional view, a separate electronics containing member useful in an alternate embodiment of the present invention.

BEST MODE FOR CARRYING OUT INVENTION

The present invention provides a microelectrochemical electrode structure 10 including an electrolytic cell 11, one embodiment of which is illustrated in FIG. 1. The electrode structure 10 includes a monolithic substrate 12 having a front surface 14 and a back surface 16 facing generally away from one another. The substrate 12 can be made of any of a number of materials but it is particularly advantageous to make the substrate 12 out of a semiconductor material such as silicon, silicon carbide, gallium arsenide, or the like. The invention, however, is more general in that the substrate 12 may also be made of a plastic material, a refractory oxide, or substantially any other material. It is even possible to make the substrate 12 of a conductive material, but in such an instance, and generally in instances in which the substrate 12 is made of a semiconductor material, it is necessary to provide an appropriate insulating layer 13 to prevent shorting through the substrate 12. For example, a silicon dioxide layer 13 can be formed by contacting a silicon substrate with wet oxygen at elevated temperature, e.g., about 1000° C.

It is important that the substrate 12 be monolithic i.e., a unitary structure formed of a single material, as this allows particularly easy construction and eliminates or greatly reduces problems of prior art devices. Particular problems which are eliminated or greatly reduced include (1) securing various chemistries to the electrodes especially when multilayered structures are required; (2) affixing the membranes that cover the chemistries in the wells; (3) leakage of electrolyte to the electronics; (4) the depositing of thick electrolytic mediums which are sometimes necessary; (5) encapsulation problems; (6) light sensitivity problems; (7) lack of versatility to do, for example, current as well as voltage measurements; (8) high cost; (9) incompatibilities of various chemistries with IC processing.

The electrochemical analysis which can be made in accordance with the methods of and/or using the sensors of the present invention includes voltammetric, potentiometric, coulombic, conductometric and AC analysis.

These problems exist for several reasons. First, the prior art devices build walls upwardly from a surface and the build up must be high enough to contain the chemistry. Second, encapsulation is difficult since the electronics are at the same surface as are the chemistries. Third, the gates of FET devices are exposed to light to which they are sensitive. Fourth, the electrolyte, being adjacent the electronics, can leak into the electronics. Fifth, since the electronics and chemistries are on the same surface the use of simple bump bonding techniques to connect sensors with electronics is precluded.

In accordance with the present invention a first well 18 extends into the substrate 12 from the front surface 14 and extends towards the back surface 16. All of the needed chemicals of the cell 11 are within the first well 18. The first well 18 ends in a first well bottom 20. A first passage 22 extends into the substrate 12 from the back surface 16 to the first well bottom 20. The first well 18 can be formed by any of a number of techniques, including, particularly, anisotropic etching carried out in accordance with the techniques of the semiconductor industry (in which instance the (100) face of the silicon corresponds to the front surface 14). Such a process includes such steps as cleaning the substrate 12, applying a photoresist layer, prebaking the layer, exposing the photoresist, developing the photoresist, rinsing the substrate 12, drying the substrate 12, and post baking it. Methods for carrying out each of such steps are known in the IC art and descriptions of such techniques may be found in, for example, "Integrated Circuit Engineering" by A. B. Glaser and G. E. Subak-Sharpe, Addison-Wesley Publishing Company, Reading, Mass., 1977. In this same text are found explanations of etching, oxidation of silicon, formation of a silicon nitride insulating layer, and the like.

An alternative way of forming well 18 (and passage 22 as well) is by laser drilling. Holes of various forms with lateral extensions from a few microns to hundreds of microns can be formed by this method. Depending on the depth, a process time, per hole formation, of less than 1 second can be involved. The silicon wet anisotropic etching technique has two major advantages over laser drilling. One, it is a parallel process whereby many holes can be made at once. Two, the surfaces are smooth and very well defined. The advantage of laser drilling is that it can provide straight but not smooth walled holes when such are desirable.

In accordance with an embodiment of the present invention a first electrode 24 is provided which is, very importantly, wholly between the front surface 14 and the back surface 16 and which extends at least to the first well 18. This is very important as this enables the securing of subsequent layers in a straight-forward fashion, makes the accommodation of the electrolytic medium in general easier (for example, eliminates spilling using an ink jet printer type of chemistry filling device), and allows for an easier fixing of additional barriers. Also better encapsulation is provided.

A first conductor 26 is provided in the first passage 22 and serves for electrically communicating the first electrode 24 to adjacent the back surface 16 of the substrate 12. The first conductor 26 is suitably an electronic, as opposed to an ionic, conductor. Alternatively, a well facing end 27 of the conductor 26 can play the role of the electrode 24. This feature makes the fabrication of the sensor 10 dramatically simpler. Often, however, the sensor electrode metal will need additional backup layers (e.g., aluminum or titanium) for strength and/or economy.

The first passage 22 can be made by any of the known techniques of the semiconductor art. For example, such techniques as anisotropic etching, laser drilling, aluminum thermomigration, and the like are useful. The first conductor 26 can be provided in the first passage 22, again by the techniques of the semiconductor art. For example, the first conductor 26 can be provided by such techniques as aluminum thermomigration, metal deposition, (evaporation or sputtering), electroless plating, electron beam evaporation, mechanical positioning of metal rods, melting in place with vacuum application, or the like. Aluminum thermomigration is a useful technique to make the metal contacts. This technique has the advantage of providing the hole and conductor in a single operation. In practice, however, the thermomigration technique is quite difficult and wet anisotropic etching followed by metal deposition is currently preferable.

Various types of electrode structures 10 can be formed. These include, for example, the Ag/AgCl reference electrode, platinum, platinum black, silver, gold, iridium, palladium, palladium/silver, iridum dioxide, platinum black/paladium, platinum oxide, and mixtures thereof, electronically conductive polymers, and generally any of the electrodes normally utilized in electrochemical measurements. Table 1 sets forth, as examples only, a short list of gases, and electrochemical systems which have been used to determine them.

In certain embodiments of the invention an electrolytic medium 28 is provided in the first well 18. The electrolytic medium 28 can be a liquid but more preferably is in the nature of a hydrogel, a plasticized polymeric membrane for potentiometric elements, an ion selective membrane, or a solid polymer electrolyte.

The needed materials for the various electrode structures 10 can be placed in the appropriate wells 18 as follows: pure metals if they need to be deposited from the front can be sputtered or evaporated, electron-beam or ohmic evaporation may be used, insoluble deposits of metal salts can be formed by chemical or electrochemical treatment of metals in situ. They can be deposited from the back as previously set forth. For providing the hydrogel one has the choice of lift off technology or ink-jet printer like technology. Solid polymeric electrolytes can be put in place in the same manner as hydrogels.

                                  TABLE 1__________________________________________________________________________                             SensitivityGas Electrocatalyst         Electrolyte                  Potential  (Detection Limit*)__________________________________________________________________________CO  Platinum-catalyzed         3.4 M H2 SO4                  1.2 V vs. NHE                             10 μA/ppm    Teflon-bonded                 (0.2 ppm)    diffusion electrodeCO  Platinoid black         Hydrated solid                  1.15 V vs. NHE                             2.2 μA/ppm    catalyst with         polymer (Nafion)    (0.9 ppm)    Teflon binder(CO)    Gold-catalyzed         4 M H2 SO4                  (1.4 V vs. NHE)                             (0.03 μA/ppm)    Teflon-bonded    diffusion electrodeNO  Gold catalyzed         4 M H2 SO4                  >1.2 V vs. NHE                             7 μA/ppm    Teflon-bonded                 (0.3 ppm)NO  Graphite with         Hydrated solid                  1.25 V vs. NHE                             2.6 μA/ppm    Teflon binder         polymer (Nafion)    (0.8 ppm)NO2    Graphite with         Hydrated solid                  0.75 V vs. NHE                             -2.9 μA/ppm    Teflon binder         polymer (Nafion)    (0.7 ppm)NO2    Gold-catalyzed         4 M H2 SO4                  <1.0 V vs. NHE                             -8 μA/ppm    Teflon-bonded                 (0.25 ppm)    diffusion electrodeH2 S    Gold-catalyzed         28% H2 SO4                  1.45 V vs. NHE                             46 μA/ppm    Teflon-bonded                 (40 ppb)    diffusion electrodeN2 H4    Gold-catalyzed         23% KOH  1.1 V vs. NHE                             40 μA/ppm    Teflon-bonded                 (50 ppb)    diffusion electrodeCH4    Teflon-bonded         2 M NaClO4 in                  0.8 V vs. Ag/AgCl                             1 μA % CH4    platinum black         γ-butyrolactane                             (3000 ppm)    electrodeO2    Gold (cathode)         Alkaline -0.6 to -1.0 V                             0.05 μA/% O2                  vs. Ag/Ag2 O anode**                             (0-100% O2)O2    Ultrathin Alkaline Lead anode**                             2.5-3 nA/ppm O2    electrode (gold?)             (0.1 ppm to 100%                             O2)H2    Platinum black         Antimonic acid                  Platinum black                             50 μA/% H2    powder             counter electrode**                             (400 ppm)__________________________________________________________________________ *Detection limit (minimum detectable quantity) is calculated as the value yielding a signalto-noise ratio of 2, using a typical noise level 1 μA of amperometric gas sensors. **Quasiamperometric (polarographic), no reference. NHE = normal hydrogen electrode.

Also, ion-selective membranes can be placed in the appropriate well(s) in the same manner as can hydrogels. Further, liquid membranes can be provided in the same manner. Composite membranes, which include enzyme based membranes, tissue cultures, living organisms, antigen-antibody and generally biocatalyst materials can also be placed in the well in the same manner.

In principle, all gases or vapors that can be electrochemically oxidized or reduced can be sensed by limiting current measurement using amperometry. The reactions occur at a characteristic potential at the electrode/electrolyte interface. An appropriate potential at which only the desired reaction proceeds must be applied to the electrode so as to obtain potential-controlled selectivity. Selectivity (or the ability to observe only one of the many possible reactions) can be either kinetic or thermodynamic in origin. Thus, the selectivity is a function of the sensing electrode catalyst and (material) potential.

An approximate indication of the suitable range of potential is provided by the reversible potentials of the reaction involved; some values are listed in Table 2. Note that each gas reaction exhibits a characteristic thermodynamic potential. An example of thermodynamic selectivity is the reduction of NO2 that occurs at low potentials (Sedlak and Blurton, 1986).

              TABLE 2______________________________________Thermodynamic PotentialsOf Reactions Involving Gases                   Thermodynamic                   Potential, E°Reaction                (mV vs. NHE*)______________________________________Oxidation reactions:HCHO + H2 O → CO2 + 4H+  + 4e-                   -123CO + H2 O → CO2 + 2H+  + 2e-                   -103H2 → 2H+  + 2e-                   0C2 H5 OH + 3H2 O → 2CO2 + 12H+  +12e-               87H2 S → S + 2H+  + 2e-                   141SO2 + 2H2 O → SO4 2-  + 4H+  + 2e-                   170HCN → 1/2C2 N2 + H+  + e=                   373CH4 + H2 O →  CH3 OH + 2H+  + 2e-                   586NO + 2H2 O → NO3 -  + 4H+  3e-                   957Reduction reactions:O3 + 2H+  + 2e-  → O2 + H2 O                   2076Cl2 + 2e-  → 2Cl-                   1360O2 + 4H+  + 4e-  → 2H2 O                   1230NO2 + H+  + e-  → HNO2                   1093CO2 + 2H+  + 2e-  → HCOOH                   -199______________________________________ *NHE = normal hydrogen electrode

Because NO2 is reduced to NO and the NO product is not further reduced, the NO2 sensor (with sensing electrode operated at low potentials) is selective for NO2, having no signal for the NO that may be present. This NO2 selectivity results from control of the sensing electrode's potential in a range such that no NO reactivity is observed. The potential of the electrochemical cell has been compared to the temperature of a catalyst surface (Blurton and Stetter, 1977), which also may be used for control of the catalyst reactivity. Control of the potential is accomplished in many sensors by using three electrodes and a potentiostatic circuit.

More exact information as to a suitable range of potentials is afforded by the kinetics of the oxidation or reduction reaction, which can be discussed only in terms of electrocatalysis. Each electrocatalyst formulation will have unique properties. The activity of platinum for CO oxidation has been found to be 103 to 106 times better than that of gold. This is a good example of kinetic selectivity. Both reactions occur on both metals, but one is orders of magnitude more rapid than the other. Although the presently available sensors utilize expensive, noble metal catalysts, the required amount of such a catalyst for each sensing element in electrode structures 10 in accordance with the present invention is minimal because the sensor is a microsize device. Moreover, inexpensive electrocatalysts based on polymer materials that exhibit catalytic activity and selectivity as high as those of noble metals can be used in place of the noble metals.

If the gas to be sensed exists in a mixture containing several reactive components that exhibit close thermodynamic selectivity potential (cf. Table 2), the concentration of the desired component can be determined selectivity by the differential pulse voltammetry (DPV) technique. Let us consider a simple example where a mixture of Gas A and Gas B exists. Gas A and Gas B would exhibit current vs. potential curves with different limiting currents IA and IB. By differentiating these curves, one obtains two sharp clearly separated peaks with different characteristic potentials, EA and EB. The peak current values are proportional to the gas concentrations. Thus, the DPV technique, in addition to an improved signal-to-noise ratio, can provide potential-controlled selectivity to an electrochemical sensor through precise measurements of Epeak values, which are closely related to the thermodynamic potentials given in Table 2 and are characteristic to each gas species.

Among useful electrolytes, particularly for amperometric elements are solid electrolytes, including solid polymeric electrolytes such as Nafion (a trademark of DuPont) which is part of a class of solid polymeric ion exchangers which conduct ions upon exposure to water. Probably the best known examples are membranes made from polystyrene with fixed negative sites (sulfonate, carboxylate or phosphonate) or fixed positive sites (quaternary ammonium or quaternary phosphonium). Selection as far as ions are concerned with these materials is almost exclusively on the basis of charge and for ions with the same charge discrimination is very slight. For amperometric sensing the use of these materials is relatively new. Other examples of solid polymeric electrolytes besides Nafion (which is a perfluorinated ionomer) are sulfonated styrene-divinyl benzene resins and divinyl napthalene sulfonic acid polymer.

Such polymers are characterized chemically and physically in that they have a hydrophobic nature with ionic (hydrophilic) clusters inside. They conduct ions upon hydration. They exclude co-ions up to the Donnan failure point at which stage ions of both types can penetrate into the resin. Neutral molecules can diffuse readily through such membranes and especially large organic molecules can dissolve within the more hydrophobic resins.

Resins can also be used as reference solutions (see, for example, French patent publication No. 2,158,905). These ion exchange resins have been used as the electrolytic medium for a potentiometric CO2 sensor (see, for example, U.S. Pat. No. 3,730,868).

For potentiometric elements membranes can comprise a polymeric binder or support impregnated with a solution of an ion selective carrier or ionophore in a solvent for the ionophore. Membranes of this type can be tailored to sense particular ions selectively. For example, for sodium the antibiotic nonactin can be used as the ionophore in a PVC matrix plasticized with dioctyl sebacate. For potassium, valinomycine would replace the nonactin.

Useful gels for incorporation within the sensor structure include, without limitation: methylcellulose, polyvinyl alcohol, agar, carboxycellulose, gelatin, agarose, deionized gelatin, polyacrylamide, polyvinyl pyrrolidone, hydroxyethylacrylate, hydroxyethylmethacrylate, and polyacrylic acid. They are characterized in that they constitute thickened (more viscous) solutions. They are hydrophilic in natural and include synthetic polymeric film forming materials.

In certain cases the electrolytic medium 28 can come from a solution being analyzed. In most cases where the electrolytic medium 28 is present, however, it is provided during the construction of the electrode structure 10. Often it will be undesirable to allow a solution being analyzed to mix with and/or directly contact the electrolytic medium 28.

A barrier 30, generally in the nature of a membrane, can cover the first well 18. The barrier 30 has an outfacing surface 32 and an infacing surface 34 and the infacing surface 34 is in flow contact with the electrolytic medium 28 so as to provide a full conductive path. Indeed, the barrier 30 can be at least partially within the first well 18. The barrier 30 provides entry into the electrolytic medium 28 of a selected moiety in response to contact of a selected species with the outfacing surface 32 of the barrier 30. Either the selected species will pass through the barrier 30 and will then constitute the selected moiety, or contact of the selected species with the barrier 30 will lead to the introduction of a different moiety into the electrolytic medium 28. The barrier 30 is generally at least substantially impermeable to the electrolytic medium 28 to prevent escape and/or mixing with the analyte solution exterior of the barrier 30. The barrier 30 would not be present, or would be permeable to a solution being analyzed, in those instances when the solution constitutes the electrolytic medium 28.

The barrier 30 may encapsulate the entire electrode structure 10 including the front surface 14 and the back surface 16. Alternatively, the barrier 30 may only cover the first well 18, or the first well 18 and part or all of the front surface 14. It may be desirable to encapsulate the remainder of the electrode structure 10, or even all of the electrode structure 10 including the barrier 30, as a protection against contamination. Generally, an inert encapsulating layer (not shown) will serve the purpose. The encapsulating layer, when present, must provide access (via, for example, pores or holes therethrough) to the first well 18 or to the barrier 30 covering the first well 18. It can be formulated as can the barrier 30.

A number of materials may serve as the barrier 30. For example, the barrier 30 can comprise a gas pervious liquid impervious membrane. This is useful in the situation wherein the sensor is used in a liquid to detect dissolved gases, for example, if the electrode structure 10 is utilized in blood.

Other types of materials for utilizing as the barrier 30 are TEFLON membranes, silicone rubber membranes, silicon polycarbonate rubber membranes, mylar, nylon 6, polyvinyl alcohol, polyvinyl chloride, methylcellulose, cellulose acetate, high density polyethylene, polystyrene, natural rubber, fluorosilicone, dimethylsilicon rubber, any appropriately perforate photoresist polymer, and dimethylsilicon. It is generally preferred that the membranes utilized be solution castable so as to make fabrication of the membrane more easily accomplished.

The barrier 30 can be placed over appropriate of the wells 18 by, for example: solution casting, separate casting on a different substrate and physical transfer, heat shrinking in place, solution casting utilizing an ink-jet printer, spin coating, or dip coating. If the barrier is in the nature of uniform latex microspheres, made for example of polystyrene, styrene-butydiene, or TEFLON, such microspheres can be placed in position utilizing the ink-jet technique, by dipping, by solvent spraying, or the like. If the barrier is of the nature of or includes activated carbon or similar materials it can be placed in position by ink-jet printing, solvent casting, or the like. If the barrier includes, for example, permanganate coated alumina or other substance which serves to remove nitric oxide, it can be placed in position similarly to the carbon particles.

The microelectrochemical electrode structure 10 just described may serve as a working or sensing electrode, a reference electrode, or a counter or auxiliary electrode. As may be seen in FIG. 2 a single substrate 12 may have one or more each of a sensing electrode cell 29, a reference electrode cell 31, and a counter electrode cell 33 thereon with appropriate provision, e.g., salt bridges 35,37, being made for ionic conductivity between the various electrode cells, or more particularly between the various electrolytic mediums 28,39,41 contacting the various electrodes. The salt bridges 35,37 are necessary when barrier 30 is a barrier for all ions.

Note that the designations S, R and C are used in the figures to indicate, respectively, sensing, reference and counter electrodes.

If the first electrode 24 is a sensing electrode the substrate 12 will also include a reference electrode 36 in ionic electrical communication with the first electrode 24. The reference electrode 36 will also be electrically isolated from the sensing electrode 24 other than via the electrolytic medium 28. For example, if the substrate is silicon an appropriate silicon dioxide or silicon nitride layer 13 can be conventionally deposited or formed in the first well 18 and in the first passage 22. The reference electrode 36 can also be provided with its own different electrolytic medium 39 (FIG. 2) containing the species which determine the reference electrode potential. Also, the counter electrode 42 can be provided with a separate electrolytic medium 41 (FIG. 2).

In the embodiment illustrated in FIGS. 3 and 4 the sensing electrode 24 and the reference electrode 36 are each in the first well 18. In such an instance the substrate 12 has a second passage 38 extending from the back surface 16 of the substrate 12 to the reference electrode 36 in the first or sensor well bottom 20. A second conductor 40 is in the second passage 38 and serves for electrically communicating the reference electrode 36 to adjacent the back surface 16 of the substrate 12. If the substrate is silicon the silicon dioxide or silicon nitride layer 13 also extends along the second passage 38.

A counter electrode 42 is provided in those instances when such is necessary, for example, for making non-potiometric measurements. The counter electrode 42 (see FIG. 3) is in ionic electrical communication with the electrolytic medium 28 and is electrically isolated from the sensing electrode 24, and from the reference electrode 36 (when such is present), other than via the electrolytic medium 28. The counter electrode 42 may be in the same well 18 as is the sensing electrode 24, as illustrated, for example, in the embodiments of FIGS. 3 and 4. And, the counter electrode 42 can, be in the same well as is the reference electrode 36 as in the embodiment of FIG. 3. The counter electrode 42 may be in the same well 18 as is the sensing electrode 24, that is it may be in the first well 18. This embodiment is seen in FIGS. 3, 4, 11, 12 and 13.

In the structure of FIG. 3 the substrate 12 has a third passage 44 extending from the back surface 16 thereof to the first well bottom 20. A third conductor 46 is located in the third passage 44 and electronically communicates the counter electrode 42 to adjacent the back: surface 16 of the substrate 12.

In the case of FIG. 4 the counter electrode 42 also plays the role of reference electrode 40. The silicon dioxide or silicon nitride layer 13 provides needed insulation.

In certain instances, for example, AC measurements, conductometric measurements, and the like, it may be desirable to have more than three electrodes in a single well 18. FIG. 5 illustrates such a structure.

In a particular instance (not shown) the well 18 can be in the nature of a trench in which electrophoresis is carried out by providing a potential gradient along the length of the trench. Appropriate sensing electrodes 24 are spaced along the bottom of the trench whereby various species can be determined. Appropriate reference 36 and/or counter electrodes 42 are also provided along the bottom of the trench.

Electronic circuitry 48 can advantageously be included in certain embodiments of the present invention in the substrate 12 adjacent the back surface 16 thereof. Such electronic circuitry 48 is adapted for, and serves for, processing signals from one or more of the sensing electrode 24, the reference electrode 36, and the counter electrode 42. The electronic circuitry 48 can be formulated by conventional integrated circuit fabrication techniques. Generally the circuitry will serve to convert the signals from high impedance to low impedance and may also amplify the signals from the electrodes, and, if desired, perform computational tasks and present the data in condition for display or printing out, for example as concentrations of the species being detected. The length(s) of the conductor(s) 26,40 and/or 46 in such instances can be kept extremely short leading to a very high signal-to-noise ratio and, therefore, increased sensitivity. Note also that the chemistry in the first well 18 is completely isolated from the electronic circuitry 48 whereby the integrity of the latter is protected.

As an alternative to having the electronic circuitry 48 on the back surface of the substrate 12, the electronic circuitry 48 can instead be on a separate semiconductor substrate 50 (see FIG. 6) which abuts the back surface 16 of the substrate 12. This provides encapsulation and protection of the electronic circuitry 48.

FIG. 7 is an enlarged view of a portion of FIG. 6. It illustrates the use of a bump bonding techniques to make the needed electrical connection between the conductor (26, 40 and/or 46) and the electronic circuitry 48. The bump bonding site 52 is spaced from the electrode (24,36 and/or 42) whereby the contents of the cells (29,31,33) are not damaged by heat during bump bonding. Also, this allows good bump bonding contact to be made whereby the resulting bond has good mechanical strength. Basically, the bump bonding is carried out by pressing the bumps 54,56 together and heating the substrate 50. The bumps 54,56 can be of very different thickness. Good results have been obtained with the bump 54 of silver and about 2000 Angstroms thick and with bump 56 of copper and about 10 microns thick.

FIG. 7 also illustrates the technique of providing the first electrode 24 by depositing a small amount of an electrode material, e.g., platinum, silver, etc., followed by depositing the first conductor 26,40,46. In such an instance the first electrode 24 forms a portion of the bottom 20 of the first well 18. Also illustrated is filling in the passage 22,38 or 44 with a support material, e.g., a polymer such as a polyimide.

In accordance with one embodiment of the present invention, for example, as illustrated in FIG. 8, the reference electrode 36 is of the nature described above. The working or sensing electrode structure 24, on the other hand, is in the nature of an ion-selective membrane 58 (as described previously) covering a sensing electrode base 60 which is attached to a sensing conductor 62 in a passage 64 which leads from a bottom 66 of the sensing electrode well 18 to the back surface 16 of the substrate 12. The analyte medium makes the electrolytic contact between the ion-selective membrane 58 and the reference electrode 36. In this instance the barrier 30 is ion transparent or can be omitted. Note that the electrolytic medium 39 is not the same material as is the ion-selective membrane 58.

Any of a number of ion selective membranes 58 can be used. For example, such membranes are disclosed by M. A. Arnold and R. L. Solsky Anal. Chem. 1986, 58, 84R-101R, M. E. Meyerhoff and Y. M. Fratecelli, Anal. Chem. 1982, 54, 27R-44R, M. A. Arnold and M. E. Meyerhoff, Anal. Chem. 1984, 20R-48R, and J. Koryta, Analytica Chimica Acta, 159, ·84, 1-46.

It is anticipated that in accordance with the present invention an array of sensing cells can be provided with occasional reference cells 36. One such array is illustrated in FIG. 9. In the particular configuration shown in FIG. 9 each reference cell 31 is surrounded by, and can serve as the reference cell 31 for, several different sensing cells 29.

It is also contemplated in accordance with the present invention that on any substrate 12 more than one sensing cell 29 can be utilized for each chemical species being analyzed. That is, there can be two or five, or ten, or any desired number of sensing cells 29 which detect, for example, carbon monoxide. This provides extra selectivity by means of chemometrics, redundancy, and reliability in case any of the carbon monoxide sensing cells 29 fail whereby the electrode structure 10 would continue to operate Chemometrics is the technique of mathematically treating data from a plurality of sensors to improve the selectivity of the analytical results (see, for example, Stetter, J. R., Jurs, P. C., and Rose, S. L., Anal. Chem. Vol. 58, pp 860-866 (1986)).

FIG. 10 illustrates an embodiment of the invention wherein a plurality of sensing cells 29 are provided, some of which can be for different constituents than others, e.g., oxygen, carbon dioxide and K+. One or more, in FIG. 10 a single reference cell 31, is also present as is a pressure sensor 70. The various cells 29,31 and the pressure sensor 70 are arranged linearly whereby the total lateral extension (width) of the array 72 of electrode structures 10 can be restricted to be no more than about 300 microns. The length of the array of the various cells 29,31 and the pressure sensor 70 is determined by the number of such cells (plus the pressure sensor 70) can be restricted to be no more than about 150 microns multiplied by the number of cells plus the number of pressure sensors 70. The pressure sensor 70 can be a conventional piezoresistive-type pressure sensor of the nature described in, for example, Borky, J. M., IEEE Trans. On. Elect. Dev. Vol. ED-26, No. 12, December 1979.

The use of a multiple array of microelectronic chemical sensors allows the quantitative detection of different gases and organic vapors to further increase selectivity, to include redundancy, to increase reliability, and to permit use of chemometrix. Also, it is possible to include different types of sensors within such an array. For example, the internal temperature of a sensor can be monitored to compensate for known parameter changes with temperature. Also, a microhumidity sensor can be incorporated.

Each microelectronic chemical sensor can comprise a different electrocatalyst coating so that each sensor is as specific as possible to a certain gas or vapor. As a result, such a sensor comprising an array of optimized microsensors exhibits a maximum selectivity to a given mixture of gases and/or vapors. The presence of extra sensor elements with the same configuration and catalysts allows not only for averaging the signals of identical elements but also for correcting signals of dissimilar elements.

All existing electrocatalytic coatings are imperfectly selective, but the extent to which they fail to be selective is different for each. If one uses an array of several microsensor devices instead of a single one and coats each with a different electrocatalyst film, the relative responses of all the microdetectors to a given gas or vapor concentration is different. The pattern of these responses is specific of a given gas or vapor (provided each microsensor exhibits reproducible signals), even if the electrocatalysts coatings are not individually sensitive to a single gas or vapor. Therefore, the sensor array can yield more information than single sensors and can be used to identify and quantify many gases and organic vapors.

Unraveling vapor spectral data from an array of microsensors in a gas or vapor detection system is possible with a microcomputer that uses innovative signal-processing techniques to overcome inherent limitations of the single sensor elements. Pattern-recognition methods can be used to determine the uniqueness of the information obtained and the capacity of each of the channels for classification. Recently, such a pattern recognition analysis of data from an electrochemical sensor array has been successfully applied for the detection of hazardous gases and vapors (Stetter, Jurs and Rose, 1986).

For the simplest case, the array containing n individual sensors that are operated amperometrically, yields n channels of data for an unknown chemical species detected. The n-channels sensor responses for each compound are normalized so that the strongest channel equals 1 (or -1, if a negative number). This normalized set of response is termed a pattern vector as follows:

Xi =(xi, x2, . . . xj, . . . xn), (4)

where Xi is the pattern vector for compound 1, and xj are the sensor responses from 1 to n. The pattern vector is concentration-independent and can be compared to a library of pattern vectors of known compounds. That with the closest match is the identified compound. The concentration can be calculated using the strongest channel of the identified pattern vector. Thus, arrays of electrode structures 10 have the capability of identifying an unknown gas or vapor from a known set of gases and vapors.

FIG. 11 illustrates a portion of the embodiment of the linear array of FIG. 10 and shows the structure of the pressure sensor 70. At the bottom of the well 18 is a flexing membrane 71 which can flex into a cavity 73 between a support 75, which may be made of any convenient material, e.g., glass, plastic or a semiconductor such as silicon. Element 70 is the pressure sensing element. Piezoresistors can be diffused in the back of the thin silicon membrane and all electronics are protected with, for example, a Mallory bonded glass piece (the support 75). The cavity 73 in the support 75 provides space for the electronics and can be evacuated to make an absolute pressure sensor possible.

FIG. 12 shows an embodiment of the invention wherein each of the sensing electrode 24 and the counter electrode 42 are in the first well 18. The reference electrode 36 communicates with the first well 18 via a pinhole 76 whereby the chemistry of the reference electrode cell 31 is kept separate from but communicates electrically with the electrolytic medium 28 in the first well 18. The reference electrode 36 is adjacent the back side 16 of the substrate 12 and is closed off by an enclosure 78 which may be merely an extension of the reference electrode 36, or which can alternatively be of a different material. The original filling of the reference cell 31 is from the back side 16 of the substrate 12.

FIG. 13 shows an embodiment of the invention wherein the sensing and counter electrodes 24,42 are in a single well 79, while the reference electrode 36 is in a separate well 81. An appropriate salt bridge 83, or its equivalent, provides ionic conductance between the electrolytic mediums 28 and 39. This is a typical structure for conductometric and voltammetric measurements, for example, a Clark oxygen sensor.

In certain instances it may be desirable to have the electronic circuitry 48 on a separate member 90 (see FIG. 14) which, via appropriate contacts 92 can form temporary electrical contact with the appropriate conductors 26,40 and/or 46 (for example, as seen in FIG. 2) during determination of the concentration or presence of one or more species. In this manner, a single member 90 can provide the needed electronic circuitry 48 for a plurality of electrode structures 10. Also, if the electrode structure 10 is used in an environment where it must be more or less permanently installed and where it has only a short useful lifetime, only the electrode structure 10 need be replaced and not the electronic circuitry 48 (since the latter need only be exposed to the environment during the actual time of measurement).

The first well 18 can be made any convenient depth. It is preferred that the first well 18 extends sufficiently towards the back surface 16 of the substrate 12 whereby the first electrode 24 is sufficiently deeply positioned within the first well 18 whereby electrochemical reaction of the selected moiety at the first electrode 24 provides a substantially Nernstian slope. In general, this means that the first well 18 should be sufficiently deep so that the electrolytic medium 28 (when present), or the membrane portion of the ion-selective electrode (when present), while remaining entirely within the first well 18, extends above the first electrode 24 a distance of at least about 40 microns.

Generally it is preferred for cells including an ion-selective membrane that the first well 18 extends towards the back surface 16 of the substrate 12 from about 40 to about 200 microns. When there is more than one electrode in the first well 18 the back surface 16 of the substrate should be close enough to the bottom of the well so that shunting does not occur between respective conductors. For example, the back surface 16 can be from about 10 to about 100 microns from the first well bottom 20. This assures very short contacts and also allows inexpensive anisotropic etching techniques (which provide tapered passages, as illustrated) to be used to form the first passage 22, and, if necessary, the second passage 38 and/or the third passage 44. As the etching is anisotropic in such an instance the widths of the passages 22, 38 and 44 at the back surface 16 could otherwise become so wide that the conductors 26, 40 and/or 46 met before or at the back surface 16.

If laser drilling is used to form the passages 22,38 and/or 44 this problem does not exist but laser drilling will not produce as many cells per unit time since the laser must be repositioned to drill each passage. However, particularly when anisotropic etching is utilized, it is preferred that the sensor well 18 extends from about 60 to about 125 microns towards the back surface 16 and it is preferred that the back surface 16 is from about 10 to about 40 microns from the sensor well bottom 20. A particularly preferred structure is one wherein the sensor well 18 is approximately 100 microns deep and the back surface 16 is about 25 microns from the sensor well bottom 20. The same preferences hold with respect to the size of the reference well and the counter well, if such is present.

For voltammetric elements and CO2 a thinner electrolytic medium 28 over the sensing electrode 24 can be more appropriate, for example, between 20 and 50 microns. Thus, the first well 18 and other wells as well can be only partially filled with the appropriate electrolytic medium 28,39,41.

The invention will be better understood by reference to the following examples which show the construction and testing of certain substructures in accordance with the present invention.

EXAMPLE 1 Macroelectrochemistry

The pH response of an IrO2 electrode was tested in physiological saline solution in the pH range 6.0-8.0. The measuring cell consisted of a 1 μm thick IrO2 electrode separated from a Ag/Cl electrode by 50 μm. The electrodes were fabricated on the surface of a silicon substrate coated with silicon dioxide. Adhesion layers were used of 100 Angstroms Ti for IrO2 and 50 Angstroms each of Ti and Pd for Ag. AgCl was formed by bringing Ag in contact with a 1% FeCl3 solution for two minutes. The potential of the Ag/AgCl electrode was first checked against a saturated calomel electrode and it agreed with the literature value. The response of the IrO2 electrode was then measured using this Ag/AgCl electrode reference.

Two electrodes gave near Nernstian responses, but third and fourth electrodes gave super- and sub-Nernstian responses, respectively. It is believed that non-optimized sputtering conditions led to the non-Nernstian electrodes and that close to 100% yield of well-behaving (Nernstian) electrodes are producible by optimizing the sputtering conditions.

EXAMPLE 2

The IrO2 electrodes of Example 1 which gave near-Nerstian response were used in the fabrication of CO2 electrodes. A 5% solution of poly(hydroxy ethyl methacrylate) in 95% ethanol was painted onto the IrO2 -AgAgCl electrode area. The solvent was allowed to evaporate. The dried polymer was equilibrated with 10-3 M NaHCO3 +0.1M NaCl. The gel and the electrolyte were then allowed to dry up. 4.75% polysiloxane-polycarbonate solution was painted on top of the gel. Again, the solvent was allowed to dry completely. The completed electrode was checked for its response to CO2. Different concentrations of CO2 were generated by adding known volumes of 0.1M NaHCO3 solution to 0.1M HCl. It was assumed that all NaHCO3 was converted to CO2. The change in potential of the electrodes was as follows:

______________________________________Concentration of CO2            Potential v. SCE______________________________________10E-5-10E-4M     38 mV10E-4-10E-3M     61 mV10E-3-10E-2M     59 mV______________________________________

These changes were reproducible to ×2 mV. The response time of the electrode was approximately 60 seconds. The response time and detection limit can be improved by controlling the thickness of the polymer membrane and the composition and thickness of the hydrogel. No attempt was done to optimize them in the planar structure.

EXAMPLE 3

Work with planar O2 sensors has determined that silver with an adhesion layer of titanium and palladium provides superior adhesion to SiO2 substrates than does platinum, and at the same time gives a current plateau similar to that of platinum. It has also been established that a two electrode system is as satisfactory as a three electrode system in giving a wide current plateau. The counter electrode in a two electrode system can be either bare Ag or Ag/AgCl. However, it was observed that a longer current plateau results using chloridized Ag. Also, the drift was considerably less in this case.

The response of the electrode was checked in phosphate and carbonate buffers. Although there was a decrease of current on shifting from phosphate to carbonate buffer a longer plateau was obtained. It has been observed by other workers that use of carbonate buffer will reduce interference from CO2.

Poly(HEMA) was chosen as the first hydrogel for testing since it has been found satisfactory by other workers. However, a new current peak at around -0.1 V was observed in the voltammogram for the electrode in the presence of poly(HEMA). It is believed that this peak is due to some impurities (residual cross-linking agent, redox initiator, etc.) which could be present in the hydrogel. In this case, purification of the hydrogel will be necessary.

After assembling all the components, the sensor was completed by casting a silicone/polycarbonate membrane over the whole structure. It was observed that the electrode decreased after this step.

EXAMPLE 4

A practical example of the current invention is a sensor for pH, CO2 and O2 in blood.

Three electrolytic cells 11 are made in a top silicon part fitting in a 20 gauge catheter. A matching bottom silicon part contains the necessary electronics. The bottom part has 10 microns high copper bumps that have been found to make a satisfactory bump bond to silver which is on the back surface 16 of the substrate 12. The sensing well 29 which is intended for pH sensing has besides the general outlook of FIG. 4 the following specifics. One electrode in the pH sensing well 29 consists of iridium dioxide and one electrode consists of Ag/AgCl. The IrO2 electrode is made by reactive sputtering through a silicon mask from the back of substrate 12. A promotion layer titanium is also sputtered on, as well as an iridium layer to make a better performing iridium/iridum dioxide electrode. Finally Ag is used to back up these layers. The order of the depositions just mentioned is as follows:

1. Titanium--50 to 100 Angstroms promotion layer

2. Iridium dioxide--2000 to 5000 Angstroms

3. Iridium--2000 to 5000 Angstroms

4. Silver--2000 Angstroms

Again the silver is there as a back-up layer and contact material to the bumps 54,56 (FIG. 7) and comes on last. In order to expose iridium dioxide to the electrolytic medium a short titanium etch is needed to free the iridium dioxide. The titanium remaining on the silicon dioxide walls after the etch helps the adhesion of iridium dioxide to the sidewalls of the passage 22. The iridium/iridium dioxide electrode was shown to give a very match with theoretical predicted potentials on a microscale. The Ag/AgCl electrode was made with the following steps:

1. Titanium--50 to 100 Angstroms of adhesion promotion

2. Palladium--50 to 100 Angstroms of adhesion promotion plus corrosion prevention

3. Silver--2000 to 3000 Angstroms

As in the case of iridium dioxide a short etch is used to expose the silver to the electrolytic medium. The Ag/AgCl was shown to behave as a microscopic Ag/AgCl reference electrode. The chlorinization was accomplished with a 1% FeCl3 solution.

The oxygen electrolytic sensing cell 29 is made in one of two fashions:

A.

1. Silver cathode

2. Ag/AgCl reference electrode

the materials fabrication is the same as mentioned above:

B.

1. Platinum cathode

2. Ag/AgCl reference electrode

3. Platinum counter-electrode

In case "A" the cathode area should be about one-fifth to one-tenth of the anode area. The best buffer solution identified for the electrolytic medium in the case of the oxygen sensor 29 is a carbonate buffer.

The material of the barrier 30 identified as a good choice for the CO2 and O2 element is a block copolymer of polycarbonate with silicone rubber. This product (e.g., General Electric MEM-213) can be heat sealed and is heat shrinkable. It can be easily solution cast. The solvents used to cast this membrane are, for example, toluene or dichloromethane.

To open up the membrane where it is not needed (i.e., the small pH cell in this case) the membrane can be locally laser cut or it can be locally dissolved. The CO2 cell 29 contains the same electrodes as the pH cell 29 except that in this case we do have an electrolytic medium, a buffer, covered by the same membrane as ;mentioned with respect to the oxygen cell.

Industrial Applicability

The present invention provides a microelectrochemical electrode structure 10, and arrays thereof on a substrate 12. Such electrode structure 10 and arrays of electrode structures 10 on a single substrate 12 are useable for detecting low concentrations of gaseous, ionic and nonionic species.

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modification, and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as fall within the scope of the invention and the limits of the appended claims.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3663409 *May 14, 1970May 16, 1972Beckman Instruments IncPressure compensation of membranetype sensors
US4020830 *Mar 12, 1975May 3, 1977The University Of UtahField effect transistor
US4062750 *Dec 18, 1974Dec 13, 1977James Francis ButlerThin film electrochemical electrode and cell
US4214968 *Apr 5, 1978Jul 29, 1980Eastman Kodak CompanyIon-selective electrode
US4225410 *Dec 4, 1978Sep 30, 1980Technicon Instruments CorporationIntegrated array of electrochemical sensors
US4259164 *Aug 13, 1979Mar 31, 1981Eastman Kodak CompanySilver/silver halide electrodes comprising chromium or nickel
US4269682 *Dec 11, 1978May 26, 1981Kuraray Co., Ltd.Having a surface coating of a hydrophobic organic polymeric membrane; miniaturization; detection and measurement of activity and concentration of ions; medical/diagnosis
US4340457 *Jan 28, 1980Jul 20, 1982Kater John A RIon selective electrodes
US4419211 *Mar 4, 1982Dec 6, 1983Lothar BrauerGas analysis sensor for measuring concentration of gas constituent
US4455213 *Dec 29, 1980Jun 19, 1984Beckman Instruments, Inc.Pressure equalization system for membrane type amperometric sensors
US4457161 *Apr 7, 1981Jul 3, 1984Hitachi, Ltd.Gas detection device and method for detecting gas
US4487679 *Mar 15, 1984Dec 11, 1984Eastman Kodak CompanyFor quantitave analysis of concentrates in biological fluids
US4502938 *Apr 8, 1982Mar 5, 1985Corning Glass WorksEncapsulated chemoresponsive microelectronic device arrays
US4528085 *Mar 15, 1983Jul 9, 1985Fuji Photo Film Company, Ltd.Ion selective electrode and process of preparing the same
US4534825 *Mar 9, 1984Aug 13, 1985Cordis Europa, N.V.Monitoring ions in blood in vivo; transistors
US4542640 *Sep 15, 1983Sep 24, 1985Clifford Paul KSelective gas detection and measurement system
US4549951 *Sep 11, 1984Oct 29, 1985Sentech Medical CorporationSimple construction; instant response, fixed slope, no electrolyteor reference
US4556474 *Jul 5, 1984Dec 3, 1985Eastman Kodak CompanyDevice for determining ionic analyte activity
US4562723 *Jul 27, 1984Jan 7, 1986Hubner Hans JMethod of and apparatus for the measurement of subterranean atmospheric parameters
US4571293 *May 9, 1985Feb 18, 1986Fuji Photo Film Co., Ltd.Multilayer composite consisting of support, electroconductive metal layer, water insoluble salt, electrolyte and ion selective layer
US4586143 *Jan 28, 1983Apr 29, 1986Hitachi, Ltd.Gas detecting apparatus
US4592824 *Sep 13, 1985Jun 3, 1986Centre Suisse D'electronique Et De Microtechnique S.A.Miniature liquid junction reference electrode and an integrated solid state electrochemical sensor including the same
US4713165 *Jul 2, 1986Dec 15, 1987Ilex CorporationSensor having ion-selective electrodes
Non-Patent Citations
Reference
1 *Y. Miyahara et al., Micro Enzyme Sensors Using Semiconductor and Enzyme Immobilization Techniques.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4975175 *Jun 15, 1989Dec 4, 1990Isao KarubeMiniaturized oxygen electrode and miniaturized biosensor and production process thereof
US5102525 *Dec 10, 1990Apr 7, 1992Hitachi, Ltd.Dielectric, gas permeable membrane stretched over electrodes, electrolytic solution
US5108926 *Sep 8, 1987Apr 28, 1992Board Of Regents, The University Of Texas SystemApparatus for the precise positioning of cells
US5111221 *Jun 27, 1990May 5, 1992United States Of America As Represented By The Secretary Of The NavyReceptor-based sensor
US5172205 *Sep 24, 1990Dec 15, 1992Nissan Motor Co., Ltd.Piezoresistive semiconductor device suitable for use in a pressure sensor
US5225374 *Jan 14, 1992Jul 6, 1993The United States Of America As Represented By The Secretary Of The NavyPorous surface over substrate protected by receptor film adhered over it
US5252294 *Feb 3, 1992Oct 12, 1993Messerschmitt-Bolkow-Blohm GmbhMicromechanical structure
US5281323 *Mar 13, 1992Jan 25, 1994Fujitsu LimitedElectrolyte composition for screen printing and miniaturized oxygen electrode and production process thereof
US5290240 *Feb 3, 1993Mar 1, 1994Pharmetrix CorporationElectrochemical controlled dispensing assembly and method for selective and controlled delivery of a dispensing fluid
US5326450 *Dec 8, 1992Jul 5, 1994Fujitsu LimitedMultilayer electrodes with electrolytes
US5331310 *Apr 6, 1992Jul 19, 1994Transducer Research, Inc.Amperometric carbon monoxide sensor module for residential alarms
US5368571 *Feb 1, 1994Nov 29, 1994Pharmetrix CorporationElectrochemical controlled dispensing assembly and method
US5368704 *Aug 6, 1993Nov 29, 1994Teknekron CorporationMicro-electrochemical valves and method
US5376255 *Sep 10, 1993Dec 27, 1994Siemens AktiengesellschaftGas sensor
US5385659 *Sep 10, 1993Jan 31, 1995Siemens AktiengesellschaftFor chemical sensors, diffusion channel
US5468408 *Nov 3, 1993Nov 21, 1995Fujitsu LimitedElectrolyte composition for screen printing and miniaturized oxygen electrode and production process thereof
US5478460 *Nov 3, 1993Dec 26, 1995Fujitsu LimitedElectrolyte composition for screen printing and miniaturized oxygen electrode and production process thereof
US5492611 *Sep 16, 1994Feb 20, 1996Fujitsu LimitedMiniaturized oxygen electrode
US5505828 *Aug 26, 1993Apr 9, 1996Via Medical CorporationCalibration solutions useful for analysis of biological fluids and methods employing same
US5554269 *Apr 11, 1995Sep 10, 1996Gas Research InstituteNox sensor using electrochemical reactions and differential pulse voltammetry (DPV)
US5573649 *Apr 28, 1995Nov 12, 1996Fujitsu LimitedMiniaturized oxygen electrode and process of producing same
US5593852 *Sep 1, 1994Jan 14, 1997Heller; AdamSubcutaneous glucose electrode
US5641644 *Dec 9, 1994Jun 24, 1997Board Of Regents, The University Of Texas SystemComputer controlled translation table coupled to solid support to position support relative to foceused stream or droplet stream of cell suspension matrix material
US5739039 *Mar 6, 1995Apr 14, 1998Ecossensors LimitedMicroelectrodes and amperometric assays
US5744697 *Aug 16, 1995Apr 28, 1998J And N Associates, Inc.Gas sensor with conductive housing portions
US5777208 *Oct 22, 1996Jul 7, 1998J And N Associates, Inc.Gas sensor with pressurized seal
US5798556 *Mar 25, 1996Aug 25, 1998Motorola, Inc.Sensor and method of fabrication
US5827948 *Jul 8, 1997Oct 27, 1998J And N Associates, Inc.Gas sensor with liquid-tight seal
US5846392 *Mar 10, 1995Dec 8, 1998Knoll; MeinhardMiniaturized circulatory measuring chamber with integrated chemo- and/or biosensor elements
US5916425 *May 16, 1996Jun 29, 1999Sendx Medical, Inc.Electronic wiring substrate with subminiature thru-holes
US5918110 *May 30, 1997Jun 29, 1999Siemens AktiengesellschaftMethod for manufacturing a combination of a pressure sensor and an electrochemical sensor
US5987965 *Oct 14, 1998Nov 23, 1999J And N Associates, Inc.Gas sensor with conductive housing portions
US6010461 *Sep 1, 1998Jan 4, 2000Sitek, Inc.Monolithic silicon intra-ocular pressure sensor and method therefor
US6022463 *May 16, 1996Feb 8, 2000Sendx Medical, Inc.Sensors with subminiature through holes
US6027760 *Dec 8, 1997Feb 22, 2000Gurer; EmirPhotoresist coating process control with solvent vapor sensor
US6040193 *Aug 4, 1998Mar 21, 2000Affymetrix, Inc.Combinatorial strategies for polymer synthesis
US6060327 *May 14, 1997May 9, 2000Keensense, Inc.Molecular wire injection sensors
US6098523 *Jul 10, 1997Aug 8, 2000Draeger Safety, Inc.Testing apparatus for gas sensors
US6110354 *Oct 31, 1997Aug 29, 2000University Of WashingtonMicroband electrode arrays
US6124102 *Apr 21, 1998Sep 26, 2000Affymetrix, Inc.Methods for determining receptor-ligand binding using probe arrays
US6136269 *Apr 21, 1995Oct 24, 2000Affymetrix, Inc.Combinatorial kit for polymer synthesis
US6146510 *May 16, 1996Nov 14, 2000Sendx Medical, Inc.Sensor cartridge for a fluid analyte analyzer
US6197506Apr 8, 1998Mar 6, 2001Affymetrix, Inc.Using substrate having over 100 different polynucleotides at density of over 50 different polynucleotides per square centimeter to generate hybridization patterns and distinguish between two nucleic acid samples; heredity; diagnosis
US6225625Jun 1, 1995May 1, 2001Affymetrix, Inc.Signal detection methods and apparatus
US6261776Apr 15, 1999Jul 17, 2001Affymetrix, Inc.Nucleic acid arrays
US6265750 *Jul 15, 1999Jul 24, 2001Teledyne Technologies IncorporatedElectrochemical gas sensor and method of making the same
US6291183Nov 17, 1999Sep 18, 2001Affymetrix, Inc.Very large scale immobilized polymer synthesis
US6305214Aug 26, 1999Oct 23, 2001Sensor Tek, LlcGas sensor and methods of forming a gas sensor assembly
US6309822Dec 23, 1996Oct 30, 2001Affymetrix, Inc.Detecting adjustments in nucleotide sequences; provide probes, mix probes with nucleic acids, detect binding of probes to preferential nucleotide sequences
US6310189Jan 25, 2000Oct 30, 2001Affymetrix, Inc.Nucleotides and analogs having photoremoveable protecting groups
US6326215Jul 30, 1999Dec 4, 2001Keensense, Inc.Molecular wire injection sensors
US6326228 *May 29, 1998Dec 4, 2001Motorola, Inc.Sensor and method of fabrication
US6329143Aug 4, 1998Dec 11, 2001Affymetrix, Inc.Providing a substrate having surface bearing multiple copies of a protective group removable on exposure to an electric field or electric current; applying electric field or current to substrate; exposing to protected monomer, repeating
US6344316Jun 25, 1997Feb 5, 2002Affymetrix, Inc.Nucleic acid analysis techniques
US6346413Nov 17, 1999Feb 12, 2002Affymetrix, Inc.Polymer arrays
US6355432Jun 2, 2000Mar 12, 2002Affymetrix Lnc.Collection of plurality of beads which have binding polymers of different target specific sequence attached thereto; said beads being coded with encoding system whereby target specific sequence of polymer attached to beads can be identified
US6358384 *Jun 20, 2000Mar 19, 2002National Draeger IncorporatedElectrochemical sensor for detecting a predetermined gas
US6379895Sep 1, 2000Apr 30, 2002Affymetrix, Inc.Photolithographic and other means for manufacturing arrays
US6395491Jun 2, 2000May 28, 2002Affymetrix, Inc.Coding and storing information on substrate; code biopolymer sequence, attach to substrate, recover information by replication of biopolymer sequence
US6403320Oct 5, 2000Jun 11, 2002Affymetrix, Inc.Support bound probes and methods of analysis using the same
US6403957Oct 16, 2000Jun 11, 2002Affymetrix, Inc.Nucleic acid reading and analysis system
US6406844Jun 1, 1995Jun 18, 2002Affymetrix, Inc.Screening an array for affinity with a receptor, two different molecules are polypeptides, amino acid sequences
US6410229Dec 14, 1998Jun 25, 2002Affymetrix, Inc.Expression monitoring by hybridization to high density nucleic acid arrays
US6416952Sep 1, 2000Jul 9, 2002Affymetrix, Inc.Photolithographic and other means for manufacturing arrays
US6420169Nov 30, 1994Jul 16, 2002Affymetrix, Inc.Device for generating preferential nucleotide sequences; for use as tools drug design
US6434420Mar 21, 2000Aug 13, 2002Integrated Biosensing TechnologiesBiopotential electrode sensory component
US6434421Mar 21, 2000Aug 13, 2002Integrated Biosensing TechnologiesBiopotential sensor electrode
US6438413Mar 21, 2000Aug 20, 2002Integrated Biosensing TechnologiesBiopotential sensor electrode system
US6440667Jul 28, 1999Aug 27, 2002Affymetrix Inc.Analysis of target molecules using an encoding system
US6441503 *Jan 3, 2001Aug 27, 2002Amkor Technology, Inc.Bond wire pressure sensor die package
US6451536Sep 27, 2000Sep 17, 2002Affymetrix Inc.Products for detecting nucleic acids
US6468740Apr 8, 1998Oct 22, 2002Affymetrix, Inc.Cyclic and substituted immobilized molecular synthesis
US6475889Apr 11, 2000Nov 5, 2002Cree, Inc.Method of forming vias in silicon carbide and resulting devices and circuits
US6491871Dec 9, 1997Dec 10, 2002Affymetrix, Inc.System for determining receptor-ligand binding affinity
US6506558Nov 29, 1995Jan 14, 2003Affymetrix Inc.Deprotecting nucleoside, nucleotide or amino acid to form polypeptide or polynucleotide
US6515303Nov 6, 2001Feb 4, 2003Cree, Inc.Method of forming vias in silicon carbide and resulting devices and circuits
US6544739Jun 2, 2000Apr 8, 2003Affymetrix, Inc.Method for marking samples
US6545264Aug 26, 1999Apr 8, 2003Affymetrix, Inc.Systems and methods for high performance scanning
US6548257Aug 22, 2001Apr 15, 2003Affymetrix, Inc.Monitoring preferential expression; provide a pool of target ribonucleic acid sequences, hybridize to immobilized probes, measure nucleic acid hybridization to soild support
US6551496Mar 6, 2001Apr 22, 2003Ysi IncorporatedMicrostructured bilateral sensor
US6551784May 9, 2001Apr 22, 2003Affymetrix IncMethod of comparing nucleic acid sequences
US6566495Dec 17, 1999May 20, 2003Affymetrix, Inc.Biosynthesis of preferential biopolymers; provide substrate, electrically activate preferential positions, bind monomer, repeat, recover biopolymers
US6576424Jan 25, 2001Jun 10, 2003Affymetrix Inc.Solid support for use in the determination, classification and mapping of biopolymer sequences
US6593669 *Jul 20, 2000Jul 15, 2003Technopuce InternationalRechargeable or non rechargeable smart battery cell and process for the production of such a cell
US6600031Apr 21, 1998Jul 29, 2003Affymetrix, Inc.Methods of making nucleic acid or oligonucleotide arrays
US6602714Nov 9, 2000Aug 5, 2003Sri InternationalViscosity and mass sensor for the high-throughput synthesis, screening and characterization of combinatorial libraries
US6610482Apr 24, 2000Aug 26, 2003Affymetrix, Inc.Sequencing, fingerprinting and mapping biological macromolecules, typically biological polymers. The methods make use of a plurality of sequence specific recognition reagents which can also be used for classification of
US6616614Sep 18, 2001Sep 9, 2003Keimar CorporationApparatus and method for ascertaining cardiac output and other parameters
US6623620Dec 17, 1999Sep 23, 2003Hathaway Brown SchoolMethod for detecting or monitoring sulfur dioxide with an electrochemical sensor
US6627154Apr 7, 1999Sep 30, 2003Cyrano Sciences Inc.Accurate differentiation and quantitation of vapors; low cost, easy to manufacture, rapid response
US6630308Dec 6, 2001Oct 7, 2003Affymetrix, Inc.Generating preferential amino acid sequences on substrate; obtain substrate, deblock, expose to amino acids, recover preferential particles
US6645359Oct 6, 2000Nov 11, 2003Roche Diagnostics CorporationBiosensor
US6646243Mar 15, 2002Nov 11, 2003Affymetrix, Inc.Fixing biopolymers to substrate; obtain substrate, incubate with nucleotide sequences, expose to activator, recover product
US6649497Nov 8, 2001Nov 18, 2003Cree, Inc.Method of forming vias in silicon carbide and resulting devices and circuits
US6660234May 15, 2002Dec 9, 2003Affymetrix, Inc.Generation of preferential nucleotide sequences on preferential substrate; obtain substrate, expose to activator, remove terminal groups, recover biopolymer
US6662439Oct 4, 1999Dec 16, 2003Roche Diagnostics CorporationAblating through metallic layer to form an interlacing electrode pattern; forming into an electrochemical biosensor strip
US6663615Sep 4, 2001Dec 16, 2003The Ohio State UniversityDual stage microvalve and method of use
US6683463 *Mar 26, 2002Jan 27, 2004Southwest Research InstituteSensor array for electrochemical corrosion monitoring
US6699667Sep 20, 2001Mar 2, 2004Keensense, Inc.Molecular wire injection sensors
US6740225Mar 6, 2001May 25, 2004Hathaway Brown SchoolElectrical thick film
US6746960Jan 18, 2002Jun 8, 2004California Institute Of TechnologyFor detection of substances/odors in the air or surrounding environment; wherein impedance, resistance, capacitance, inductance, or other electrical property of sensor is determined; integrated circuits
US6747143May 20, 2002Jun 8, 2004Affymetrix, Inc.Preparation of sequences on substrate; obtain substrate, deposit on plate surface, incubate with activator, remove protective groups, recover biopolymer
US6770322 *Mar 2, 2001Aug 3, 2004Ysi IncorporatedLaser drilling at least one frustoconical pore in said film such that said pore has a large diameter portion and a small diameter portion
US6770503Oct 21, 1999Aug 3, 2004The Charles Stark Draper Laboratory, Inc.Integrated packaging of micromechanical sensors and associated control circuits
US6790341Aug 29, 2000Sep 14, 2004University Of WashingtonMicroband electrode arrays
US6849168Nov 9, 2001Feb 1, 2005Kval, Inc.Electrochemical microsensor package
US6849462May 26, 2000Feb 1, 2005Affymetrix, Inc.Producing arrays by depositing a resist on a substrate, removing a portion of the resist to expose localized areas, dispensing a monomer to occupy a localized area of the surface of the support, allowing the monomer to bind
US6864101May 26, 2000Mar 8, 2005Affymetrix, Inc.Combinatorial strategies for polymer synthesis
US6866758Mar 21, 2002Mar 15, 2005Roche Diagnostics CorporationBiosensor
US6896778Jun 4, 2001May 24, 2005Epocal Inc.Electrode module
US6911621Jan 8, 2003Jun 28, 2005Roche Diagnostics CorporationBiosensor
US6919211Sep 1, 2000Jul 19, 2005Affymetrix, Inc.Solid support comprising amino acid sequences for sequencing, fingerprinting and mapping biological macromolecules; structure and function analysis
US6927032Jan 28, 2003Aug 9, 2005Affymetrix, Inc.Expression monitoring by hybridization to high density oligonucleotide arrays
US6939451Aug 24, 2001Sep 6, 2005Aclara Biosciences, Inc.Substrate having channel and aperture in fluid communication with channel, cover bonded to substrate such that reservoir is formed at aperture, electroconducting ink pattern on substrate or cover to make electrical contact with test material
US6943034Feb 4, 2000Sep 13, 2005Affymetrix, Inc.Combinatorial strategies for polymer synthesis
US6946739Apr 10, 2003Sep 20, 2005Cree, Inc.Layered semiconductor devices with conductive vias
US6955915Dec 14, 2001Oct 18, 2005Affymetrix, Inc.Solid phase synthesis; photolithography
US6979544Feb 2, 2004Dec 27, 2005Keensense, Inc.Molecular wire injection sensors
US6987396Jan 26, 2004Jan 17, 2006Southwest Research InstituteSensor array for electrochemical corrosion monitoring
US7033840Nov 9, 2000Apr 25, 2006Sri InternationalReaction calorimeter and differential scanning calorimeter for the high-throughput synthesis, screening and characterization of combinatorial libraries
US7061061Oct 24, 2002Jun 13, 2006California Institute Of TechnologyTechniques and systems for analyte detection
US7070590Sep 19, 2000Jul 4, 2006Massachusetts Institute Of TechnologyMicrochip drug delivery devices
US7070592 *Jul 7, 2004Jul 4, 2006Massachusetts Institute Of TechnologyMedical device with array of electrode-containing reservoirs
US7073246Jun 20, 2003Jul 11, 2006Roche Diagnostics Operations, Inc.Method of making a biosensor
US7087732Dec 28, 2001Aug 8, 2006Affymetrix, Inc.Nucleotides and analogs having photoremovable protecting groups
US7097751 *Aug 28, 2002Aug 29, 2006Kabushiki Kaisha ToshibaBase sequence detecting electrode, base sequence detecting device and base sequence detecting method
US7101472Mar 13, 2003Sep 5, 2006The Charles Stark Draper Laboratory, Inc.Microfluidic ion-selective electrode sensor system
US7104517 *Jun 30, 2000Sep 12, 2006Gyros Patent AbPolymer valves
US7125786Feb 25, 2005Oct 24, 2006Cree, Inc.Method of forming vias in silicon carbide and resulting devices and circuits
US7179355 *Feb 19, 2003Feb 20, 2007Alphasense LimitedElectrochemical cell
US7220550Oct 25, 2005May 22, 2007Keensense, Inc.Molecular wire injection sensors
US7287318Nov 7, 2003Oct 30, 2007Roche Diagnostics Operations, Inc.Biosensor
US7309414Apr 8, 2005Dec 18, 2007Southwest Research InstituteMethod for measuring localized corrosion rate with a multi-electrode array sensor
US7323298Jul 30, 1996Jan 29, 2008The Board Of Trustees Of The Leland Stanford Junior UniversityMicroarray for determining the relative abundances of polynuceotide sequences
US7378236Aug 14, 1995May 27, 2008The Board Of Trustees Of The Leland Stanford Junior UniversityMethod for analyzing gene expression patterns
US7386937May 1, 2006Jun 17, 2008Roche Diagnostics Operations, Inc.Method of making a biosensor
US7407570Mar 13, 2003Aug 5, 2008The Charles Stark Draper Laboratory, Inc.Disposable, self-administered electrolyte test
US7442499Nov 24, 1998Oct 28, 2008The Board Of Trustees Of The Leland Stanford Junior UniversityPolynucleotides fluorescently labeled, contacted under hybridization conditions with array of different DNA sequences at discrete locations on nonporous surface; fluorescence level of each array sequence is measure of concentration
US7445766Apr 10, 2006Nov 4, 2008Microchips, Inc.Miniaturized device; substrate with reservoirs, openings; barriers layer covering aperture
US7476827Oct 29, 2004Jan 13, 2009Roche Diagnostics Operations, Inc.Method of making a biosensor
US7550310May 24, 2006Jun 23, 2009California Institute Of TechnologyTechniques and systems for analyte detection
US7563623 *Feb 21, 2007Jul 21, 2009Fujifilm Corporationnonspecific adsorption is less likely; a large amount of protein can be immobilized by having a hydrogel (polysaccharide) bind to biosensor via a SAM (self-assembled monolayer) compound (aminoalkanethiol) having high water solubility and good performance in terms of supply; surface plasmon resonance
US7570992Jan 13, 2004Aug 4, 2009Genetronics, Inc.Electrical field therapy with reduced histopathological change in muscle
US7630747Sep 9, 2003Dec 8, 2009Keimar, Inc.Apparatus for ascertaining blood characteristics and probe for use therewith
US7664607Oct 4, 2005Feb 16, 2010Teledyne Technologies IncorporatedPre-calibrated gas sensor
US7691330May 26, 2000Apr 6, 2010Affymetrix, Inc.Substrate is contacted by a channel block having channels through which selected reagents are delivered; the substrate is rotated by a rotating stage and the process is repeated to form arrays of products on the substrate; may be combined with light-directed methodolgies
US7718048Jun 14, 2006May 18, 2010Kabushiki Kaisha Toshibabase sequence detecting electrode, a base sequence detecting device and a base sequence detecting method for specifically detecting a specific gene existing in a sample; precisely carries out detection of current based on an interaction with a target base sequence
US7736309 *Dec 31, 2002Jun 15, 2010Medtronic Minimed, Inc.Implantable sensor method and system
US7736906Jun 17, 2002Jun 15, 2010Affymetrix, Inc.Preparing olionucleotide and/or peptide sequences on single substrate
US7770436 *Nov 6, 2007Aug 10, 2010Rheosense, Inc.Micro rheometer for measuring flow viscosity and elasticity for micron sample volumes
US7780827Jun 22, 2005Aug 24, 2010Roche Diagnostics Operations, Inc.Biosensor
US7814773 *Feb 24, 2006Oct 19, 2010Tsinghua UniversityReference leak
US7824529Jan 25, 2005Nov 2, 2010Epocal Inc.Electrode module
US7833395 *Jan 17, 2005Nov 16, 2010Adamant Technologies SaElectrically conducting material pierced by a regular array of cavities; a measurement electrode formed of connected and electrically conducting microdisks, a generator electrode formed from an electrically conducting plate
US7892221Jan 21, 2005Feb 22, 2011Massachusetts Institute Of TechnologyMethod of controlled drug delivery from implant device
US7892849Feb 20, 2009Feb 22, 2011Roche Diagnostics Operations, Inc.Reagent stripe for test strip
US7892974Oct 20, 2006Feb 22, 2011Cree, Inc.Method of forming vias in silicon carbide and resulting devices and circuits
US7901397Oct 31, 2007Mar 8, 2011Massachusetts Institute Of TechnologyMethod for operating microchip reservoir device
US7918842Feb 20, 2004Apr 5, 2011Massachusetts Institute Of TechnologyMedical device with controlled reservoir opening
US7922709Nov 30, 2005Apr 12, 2011Genetronics, Inc.Enhanced delivery of naked DNA to skin by non-invasive in vivo electroporation
US7985386Sep 29, 2008Jul 26, 2011Microchips, Inc.Implantable medical device for diagnostic sensing
US8123922Sep 7, 2007Feb 28, 2012University Of Utah Research FoundationNanopore based ion-selective electrodes
US8181531Jun 27, 2008May 22, 2012Edwin CarlenAccessible stress-based electrostatic monitoring of chemical reactions and binding
US8202796Feb 7, 2011Jun 19, 2012Cree, Inc.Method of forming vias in silicon carbide and resulting devices and circuits
US8236493Aug 7, 2008Aug 7, 2012Affymetrix, Inc.Methods of enzymatic discrimination enhancement and surface-bound double-stranded DNA
US8266795Oct 22, 2007Sep 18, 2012Sensorcon, Inc.Methods of making an electrochemical gas sensor
US8292808Sep 16, 2008Oct 23, 2012Medtronic Minimed, Inc.Implantable sensor method and system
US8414489 *Jan 12, 2005Apr 9, 2013Medtronic Minimed, Inc.Fabrication of multi-sensor arrays
US8465466Nov 22, 2004Jun 18, 2013Medtronic Minimed, IncMethod and system for non-vascular sensor implantation
US8506550Nov 24, 2005Aug 13, 2013Medtronic Minimed, Inc.Method and system for non-vascular sensor implantation
US8649840Jun 6, 2008Feb 11, 2014Microchips, Inc.Electrochemical biosensors and arrays
US8728289 *Dec 15, 2005May 20, 2014Medtronic, Inc.Monolithic electrodes and pH transducers
US20090184000 *Dec 21, 2006Jul 23, 2009Brenneman Allen JElectrochemical Sensor System Using a Substrate With at Least One Aperture and Method of Making the Same
US20100230697 *Aug 11, 2008Sep 16, 2010Osram Opto Semiconductors GmbhOpto-electronic semiconductor module and method for the production thereof
US20120138458 *Jan 20, 2012Jun 7, 2012Research & Business Foundation Sungkyunkwan UniversityCell-based transparent sensor capable of real-time optical observation of cell behavior, method for manufacturing the same and multi-detection sensor chip using the same
DE19924856A1 *May 31, 1999Dec 21, 2000Intermedical S A HSensor monitoring temperature, pressure and change in hydrogen peroxide concentration within sterilization and disinfection container has two electrodes linked by hydrophilic polymer-coated membrane
EP0506305A2 *Mar 19, 1992Sep 30, 1992Fujitsu LimitedElectrolyte composition for screen printing and miniaturized oxygen electrode and production process therefor
EP0743517A1 *Mar 19, 1992Nov 20, 1996Fujitsu LimitedMiniaturized oxygen electrode and production process thereof
EP0886330A1 *Jun 19, 1998Dec 23, 1998Imra America, Inc.Process for filling electrochemical cells with electrolyte
EP1549242A2 *Sep 15, 2003Jul 6, 2005Medtronic MiniMed, Inc.Implantable sensor method and system
EP2159571A1Jun 4, 2002Mar 3, 2010Epocal Inc.Diagnostic device with electrode module
WO1994017850A1 *Feb 1, 1994Aug 18, 1994Pharmetrix CorpElectrochemical controlled dispensing assembly and method
WO1999053287A2 *Apr 7, 1999Oct 21, 1999California Inst Of TechnElectronic techniques for analyte detection
WO2001014866A1 *Aug 22, 2000Mar 1, 2001Llobet Jordi AguiloSilicon-based multisensor microsystem
WO2002006789A2 *Jul 13, 2001Jan 24, 2002Leonidas G BachasMultimeric biopolymers as structural elements, sensors and actuators in microsystems
WO2008030582A2 *Sep 7, 2007Mar 13, 2008Richard B BrownNanopore based ion-selective electrodes
WO2010045458A1 *Oct 15, 2009Apr 22, 2010University Of Memphis Research FoundationMethod and device for detection of analyte in vapor or gaseous sample
WO2010056101A1 *Nov 13, 2008May 20, 2010Advanced Bio-Med Tools Sdn. Bhd.An oxygen sensor
WO2011049427A1 *Nov 11, 2009Apr 28, 2011Mimos BerhadMethod of fabricating integrated reference electrode
Classifications
U.S. Classification204/412, 257/414, 204/416, 204/408
International ClassificationB01J35/02, G01N27/27, G01N27/404, G01N27/403
Cooperative ClassificationG01N27/403
European ClassificationG01N27/403
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